Biology subjects

Stammers, M.

Publications and source records attributed to Stammers, M..

4 recordsLinked to original sources

bioRxiv2025

Embryonic stem cell factors DPPA2/4 facilitate a unique chromatin state in non-small cell lung cancer

Embryonic regulators are often re-expressed in cancers, however the functional and molecular significance of this is not always understood. The epigenetic priming factors Developmental Pluripotency Associated 2 and 4 (DPPA2/4) have crucial roles in early development and are implicated in cancer pathogenesis. We reveal in non-small cell lung cancer (NSCLC), DPPA2/4 co-expression is associated with poorly differentiated tumours, impaired patient outcomes and accelerated in vivo xenograft tumour growth. Proteomic analyses reveal DPPA2/4 dimerise to enhance their protein stability and binding efficiency to nucleosomes. Our multiomic epigenomic analysis uncovered novel functions for DPPA2/4 in facilitating a unique chromatin landscape in NSCLC cells at active promoters and enhancers. These domains are simultaneously marked by active H3K4me3, PRC1 deposited H2AK119Ub but devoid of PRC2 deposited H3K27me3. This paradoxical uncoupling between the activity of the Polycomb Repressive Complexes is likely driven by H3K27ac at these regions that prevents PRC2 catalytic activity but not recruitment. Our results demonstrate how in NSCLC cells, DPPA2/4 promote a "poised for repression" chromatin state, uncoupling complex recruitment from catalytic activity. Our study highlights how aberrant re-activation of embryonic factors in cancers may take on new functions, promoting tumourigenesis.

molecular biology↗

bioRxiv2025

RNA helicase DDX1 regulates germinal centre selection and affinity maturation by promoting tRNA ligase activity

Clonal expansion of antigen-specific B-cells defines effective germinal centre responses and is key for the generation of high-affinity antibodies. While positive selection in germinal centres has been associated with anabolic metabolism and cell growth, the downstream drivers of B-cell proliferation are not well understood. Here we report that the RNA helicase DDX1 is required for germinal centre maturation and accrual of dark-zone cellularity. Upon interaction with T-follicular helper cells, DDX1-deficient B-cells upregulate c-MYC but do not clonally expand. We show that positive selection is coupled with an increase in mRNA translation, that is dependent on DDX1. DDX1 endows B-cells with the protein biosynthetic capability that is required for rapid cell proliferation. It does so by modulating the activity of the tRNA ligase complex and tRNA splicing. Our data reveal that mRNA translation efficiency is a key determinant of B-cell fitness during germinal centre responses.

immunology↗

bioRxiv2024

RNA-binding proteins control the G2-M checkpoint of the germinal centre B cell

How germinal centre (GC) B cells undergo rapid cell division while maintaining genome stability is poorly understood. Here, we show that the RNA-binding proteins ZFP36L1 and ZFP36L2 act downstream of antigen-sensing and protect GC B cells from replication stress by controlling a cell cycle-related RNA post-transcriptional regulon. ZFP36L1 and ZFP36L2 safeguard faithful completion of mitosis by restraining the expression of CDK1 and cyclin B1, whilst controlling their activity through regulation of a p21-mediated negative feedback loop. In the absence of ZFP36L1 and ZFP36L2, GC B cells arrest in G2-M and die by apoptosis, resulting in curtailed GC responses. This is associated with stalling of the DNA replication fork at active replication initiation zones, which causes replication stress and increased activity of the ATR/CHK1 DNA damage response. Our findings reveal that gene regulation by RNA-binding proteins is essential for a functional G2-M checkpoint to operate in GC B cells.

immunology↗

bioRxiv2023

ERK signalling orchestrates metachronous transition from naive to formative pluripotency

Naive epiblast cells in the embryo and pluripotent stem cells in vitro undergo developmental progression to a formative state competent for lineage specification. During this transition, transcription factors and chromatin are rewired to encode new functional features. Here, we examine the role of mitogen-activated protein kinase (ERK1/2) signalling in pluripotent state transition. We show that a primary consequence of ERK activation in mouse embryonic stem cells is elimination of Nanog, precipitating breakdown of the naive state gene regulatory network. Cell variability in pERK dynamics results in metachronous down-regulation of Nanog and naive state exit. Knockdown of Nanog allows exit without ERK activation. However, transition to formative pluripotency does not proceed and cells collapse to an indeterminate identity. This failure is attributable to loss of expression of the central pluripotency factor Oct4. Thus, during formative transition ERK signalling both dismantles the naive state and preserves pluripotency. These results illustrate that a single signalling pathway can both drive exit from a developmental state and safeguard progression to the successor state.

developmental biology↗